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Videx Case Study

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Videx Case Study

  1. 1.   1   Oops I “did” It Again: The Reformulation of didanosine PHCY 512: Pharmaceutics and Drug Delivery Systems February 15, 2016 Patrick Kurunwune
  2. 2.   2   Section 1 – Background Information Many drug manufacturers target the stomach as to where a given drug will be absorbed. The reason for this is that the stomach of the gastrointestinal tract has a pH of around 1.0 – 5.4 (depending on a number of various factors) (1). The problem that drug manufacturers run into is that at such low pH levels, a drug will be absorbed in the stomach as it goes through the GI tract even though that may not be the intended site of absorption. So what drug manufacturers have done to alleviate this problem of “pre mature absorption” is to coat their tablets with an enteric coat. An enteric coat is designed to be absorbed in the basic environments of the small intestine (2). Enteric coating consists of a sugar core that is engulfed by the active pharmaceutical ingredient (API). Engulfing the API is then the enteric coating. The enteric coating is built to not dissolve at low pHs, but will dissolve in higher pHs. The drug Videx (generic name is didanosine) is a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV) (3). Didanosine is unstable in acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes (3). Videx has many different formulations. It has a pediatric powder for oral solution as well as an enteric-coated capsule formulation. However, the drug company who produced this drug, Bristol- Myers Squibb didn’t initially formulate this drug with an enteric coating. That is the case that will be discussed. Section 2 – Primary Literature Summary In this case, the drug company, Bristol-Myers Squibb originally did not want didanosine to be absorbed in the stomach where the pH was so low. Therefore, they originally decided to formulate their drug with antacids to prevent acid hydrolysis of the drug while in the stomach (2). The only problem with this is that users of this formulation reported side effects of diarrhea, nausea, and GI disturbances. This original formulation was in tablet form, so Bristol- Myers Squibb decided to formulate an EC capsule to see if this would reduce the GI side effects that were being experienced by their users. In February of 2000, a six-week open label crossover study was conducted. Participants included HIV-infected men and women (older than 18 years old) taking didanosine tablets either once or twice daily, for four or more weeks (2). The participants were asked to rate how severe symptoms of nausea, bloating, GI upset, diarrhea, abdominal cramps, and flatulence were on a scale from 0-6 (6 being the most severe). They were to be placed on the didanosine tablet for two weeks and then were to switch over to the didanosine EC capsules for the remainder of the 6 weeks. After the six weeks, the severity scores were lower across all of the six different symptoms. This can be seen in Figure 1. The striking tolerability advantages appear to support routine switching to EC for such patients and may suggest that widespread preferential selection of the EC form is appropriate to enhance didanosine tolerability and promote treatment adherence (2). After the study was completed, all 42 of the participants preferred the didanosine EC to the didanosine tablet. Section 3 – Original Discussion This case explicitly explains how pharmaceutics can play an instrumental role in treatment efficacy for patients. The didanosine tablets probably had less adherence due to all of the side effects that were associated with it. The decreased adherence long term may cause physicians to prescribe a different drug that has fewer side effects. Negative reviews from patients is probably what caused Bristol-Myers Squibb to go back and
  3. 3.   3   continue to reformulate their drug. Since there is some bacterial flora present in the ileum of the small intestines an alternative solution could have been to attach polymers that can only be cleaved by those bacteria (1). That would prevent absorption in the stomach, and will better aid in the absorption in the small intestines. However, a problem with this alternative method is that those polymers that are broken down by bacterial flora may have increased the overall size of the didanosine formulation, or distort the taste making the drug less palatable. Larger pills and a distorted taste could also decrease the adherence to specific medications. Also, adding polymers that can be cleaved by bacteria is a feature that is used more for absorption in the large intestines than the small intestines. When critically evaluating the case, the didanosine EC formulation was clearly the better choice. However, out of 42 individuals who completed the study, 45% had undetectable HIV RNA. Also, the mean CD4 cell count was 506 cells. A healthy range is between 500-1200 cells (4). The use of antidiarrheal medications declined from 26 total doses in week 2 (on tablets) to 11 doses in week 4 (on capsules) (2). This data could be misleading because it is possible that since 45% of participants did not even have any detectable HIV RNA, their cellular functions and body’s ability to function at a certain rate were working more efficiently than the 55% who had detectable HIV RNA. Therefore, the decrease in antidiarrheal medications decreased by a little less than half because half of the participants had a healthier overall system. Also, the CD4 cell count is still within the range of a healthy individual. A follow up study should be done where all of the individuals have detectable HIV RNA as well as an overall lower mean CD4 cell count to test if a decline in GI side effects is negligible in the later stages of HIV.
  4. 4.   4   References 1. Jay M. Drug Formulation and Oral Dosage Form. Slide 4. Date accessed: February 14, 2016 2. Kunches LM, Reinhalter NE, Marquis A, Coakley E, Cohen C, Morris AB, Mazzullo JM. Tolerability of enteric coated didanosine capsules compared with didanosine tablets in adults with HIV infection. J Acquir Immune Defic Syndr. 2001 Oct 1;28 (2):150-3. PubMed PMID: 11588508. 3. Didanosine." (n.d.): n. pag. Videx Packet Insert. Bristol-Myers Squibb Company, Aug. 2016.Web. http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020154s50,20155 s39,20156s40,21183s16lbl.pdf. Accessed February 14, 2016. 4. CD4 Count." CD4 Count. AIDS.gov, 09 Sept. 2015. Web. <https://www.aids.gov/hiv- aids-basics/just-diagnosed-with-hiv-aids/understand-your-test-results/cd4-count/. Accessed February 14, 2016 Figure 1: Patients diary score for gastrointestinal symptoms on didanosine tablet or didanosine EC capsule. Taken from Kunches LM, Reinhalter NE, Marquis A, Coakley E, Cohen C, Morris AB, Mazzullo JM. Tolerability of enteric-coated didanosine capsules compared with didanosine tablets in adults with HIV infection. J Acquir Immune Defic Syndr. 2001 Oct 1;28(2):150-3. PubMed PMID: 11588508.
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